Transformative research on the normal and Alzheimer's disease brain through studies of neuronal gene recombination

项目摘要/摘要 了解人脑及其疾病是一个巨大的挑战，但也是一个机会 改善人类健康。在正常大脑的许多显著属性中，它存储和 为一生的学习和记忆找回信息，仍然是生活的乐趣和谜团之一。阿尔茨海默氏症 疾病(AD)扰乱了这些认知功能，并造成了巨大的个人、家庭和社会成本， 尽管有数十种科学理论，但令人不安的是缺乏治疗疾病的方法，数十亿美元 耗资巨大，数十年的研究，以及数百项失败的临床试验。 这一变革性的提议将通过对一种新发现的分子的研究来应对这些挑战 脑内机制：神经元基因重组(NGR)。NGR可能会改变内部的单个基因组 通过将神经活动-包括正常和异常-与内部功能DNA基因序列联系起来，每个神经元 有丝分裂后神经元的基因组，通过RNA序列的反向插入过程来产生 基因组DNA(GencDNA)。由此产生的只有一个基因的数千个基因变异--AD基因 APP-为疾病进展和迄今为止AD疗法的徒劳提供了新的解释。三个领域 研究将由一支由世界级生物信息学授权的经验证的调查人员团队进行， 阿尔茨海默氏症和神经科学专家。首先，我们将定义人脑中NGR的机制 通过识别相关基因并对其功能进行生化表征。第二，我们将正式界定 NGR与主要形式的AD和治疗学的相关性通过分析足够数量的零星AD大脑， 以及检查与家族性阿尔茨海默病和唐氏综合症的关系，以确定共同的分子 病因学。这些研究还将通过研究FDA批准的研究来检验AD的潜在近期治疗方法 逆转录酶抑制剂及其对AD终点的影响，这将建立在科学的基础上 基于NGR的基础。第三，我们将使用有针对性和不偏不倚的方法来识别新的NGR基因 以及它们与其他脑部疾病的关系，特别是那些涉及散发性脑部疾病的疾病 广告。这些研究是第一次检查NGR，这代表了一条没有NIH先前支持的新研究路线， 在不服从标准NIH机制的范围内，对大脑进行真正的变革性研究，其 疾病，以及AD的巨大挑战。

Project Summary/Abstract Understanding the human brain and its diseases represents an enormous challenge but also an opportunity for bettering human health. Among the many remarkable attributes of the normal brain, its ability to store and retrieve information for a lifetime of learning and memories, remains one of life’s joys and mysteries. Alzheimer’s disease (AD) disrupts these cognitive functions and has enormous personal, familial, and societal costs, compounded by a disturbing absence of disease-modifying therapies despite scores of scientific theories, billions of dollars, decades of research, and hundreds of failed clinical trials. This transformative proposal will meet these challenges through studies on a newly identified molecular mechanism within the brain: neuronal gene recombination (NGR). NGR may alter individual genomes within each neuron by linking neural activity – both normal and abnormal – to functional DNA gene sequences within the genomes of post-mitotic neurons, doing so through a process of retro-insertion of RNA sequences to produce genomic cDNAs (gencDNAs). The resulting thousands of gene variants for just a single gene – the AD gene APP – offers new explanations for disease progression and the futility of AD therapeutics thus far. Three areas of study will be pursued with a team of proven investigators empowered by world class bioinformatics, Alzheimer’s disease, and neuroscience experts. First, we will define the machinery of NGR in the human brain by identifying involved genes and biochemically characterizing their function. Second, we will formally define NGR relevance to major forms of AD and therapeutics by analyses of a sufficient number of sporadic AD brains, as well as examining relationships to familial AD and Down syndrome towards identifying shared molecular etiologies. These studies will also examine a potential near-term therapy for AD by studying FDA-approved reverse transcriptase inhibitors and their impact on AD endpoints, which would be grounded in a scientific foundation based upon NGR. Third, we will use targeted and unbiased approaches to identify new NGR genes and their relationships to other brain diseases, particularly those involved with sporadic brain disorders beyond AD. These studies are the first to examine NGR, representing a new line of research without prior NIH support, with a scope not amenable to standard NIH mechanisms, towards truly transformational studies of the brain, its diseases, and the enormous challenge of AD.